Resistance to poly adenosine diphosphate(ADP)-ribose polymerase inhibitor(PARPi)presents a considerable obstacle in the treatment of ovarian cancer.F-box and tryptophan-aspartic(WD)repeat domain containing 11(FBXW11)m...Resistance to poly adenosine diphosphate(ADP)-ribose polymerase inhibitor(PARPi)presents a considerable obstacle in the treatment of ovarian cancer.F-box and tryptophan-aspartic(WD)repeat domain containing 11(FBXW11)modulates the ubiquitination of growth-and invasion-related factors in lung cancer,colorectal cancer,and osteosarcoma.The function of FBXW11 in PARPi therapy is still ambiguous.In this study,RNA sequencing(RNA-seq)showed that FBXW11 expression was raised in ovarian cancer cells that had been treated with PARPi.FBXW11 was abnormally expressed at low levels in high-grade serous ovarian cancer(HGSOC)tissues,and low levels of FBXW11 were associated with shorter overall survival(OS)and progression-free survival(PFS)in HGSOC patients.Overexpressing FBXW11 made ovarian cancer more sensitive to PARPi,while knocking down FBXW11 made it less sensitive.The four-dimensional(4D)label-free quantitative proteomic analysis revealed that FBXW11 targeted S100 calcium binding protein A11(S100A11)and promoted its degradation through ubiquitination.The increased degradation of S100A11 led to less efficient DNA damage repair,which in turn contributed to increased PARPi-induced DNA damage.The role of FBXW11 in promoting PARPi sensitivity was also confirmed in xenograft mouse models.In summary,our study confirms that FBXW11 promotes the susceptibility of ovarian cancer cells to PARPi via affecting S100A11-mediated DNA damage repair.展开更多
F-box and WD-40 domain protein 11(FBXW11)is an important component of the E3 ubiquitin-ligase enzyme that plays a key role in the ubiquitin-dependent regulation of spermatogenesis.In our previous research,the mRNA exp...F-box and WD-40 domain protein 11(FBXW11)is an important component of the E3 ubiquitin-ligase enzyme that plays a key role in the ubiquitin-dependent regulation of spermatogenesis.In our previous research,the mRNA expression of FBXW11 in bull sperm with high motility is significantly higher than that with low motility.In the present study,the protein expression levels of FBXW11 in bull testicular tissues with low-performance sperm quality groups were significantly higher than those in normal performance groups.The immunohistochemistry result demonstrated that FBXW11 protein was located in the periphery of Leydig cells and seminiferous tubules.Three splice variants of the FBXW11 gene,namely,FBXW11-tv1,FBXW11-tv2,and FBXW11-tv3,were identified in testicular tissues.The splicing patterns of the three variants are exon skipping.The transcript FBXW11-tv2 expressions were the highest in each sample.The low-performance groups displayed higher FBXW11-tv1 and FBXW11-tv2 transcript expressions than the normal performance groups.Two CpG islands were located within the 5’UTR and exon 1-2 region of the FBXW11 gene.Bisulfite sequencing PCR results demonstrated that the methylation levels of 11 methylation sites in the CpG island 2 from−99 to−43 in the normal performance groups were significantly lower than those in the low-performance groups.Pearson correlation analysis suggested that the CpG island 2 methylation level was negatively correlated with sperm motility and the transcript FBXW11-tv2 expression level.Our data revealed that alternative splicing and DNA methylation jointly regulated FBXW11 gene expression and were correlated with sperm quality traits during spermatogenesis in Holsteins.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:81972440 and 82002740)the Natural Science Foundation of Shaanxi Province,China(Grant No.:2024JC-ZDXM-52).
文摘Resistance to poly adenosine diphosphate(ADP)-ribose polymerase inhibitor(PARPi)presents a considerable obstacle in the treatment of ovarian cancer.F-box and tryptophan-aspartic(WD)repeat domain containing 11(FBXW11)modulates the ubiquitination of growth-and invasion-related factors in lung cancer,colorectal cancer,and osteosarcoma.The function of FBXW11 in PARPi therapy is still ambiguous.In this study,RNA sequencing(RNA-seq)showed that FBXW11 expression was raised in ovarian cancer cells that had been treated with PARPi.FBXW11 was abnormally expressed at low levels in high-grade serous ovarian cancer(HGSOC)tissues,and low levels of FBXW11 were associated with shorter overall survival(OS)and progression-free survival(PFS)in HGSOC patients.Overexpressing FBXW11 made ovarian cancer more sensitive to PARPi,while knocking down FBXW11 made it less sensitive.The four-dimensional(4D)label-free quantitative proteomic analysis revealed that FBXW11 targeted S100 calcium binding protein A11(S100A11)and promoted its degradation through ubiquitination.The increased degradation of S100A11 led to less efficient DNA damage repair,which in turn contributed to increased PARPi-induced DNA damage.The role of FBXW11 in promoting PARPi sensitivity was also confirmed in xenograft mouse models.In summary,our study confirms that FBXW11 promotes the susceptibility of ovarian cancer cells to PARPi via affecting S100A11-mediated DNA damage repair.
基金supported by the Major Project of National Transgene in China(2018ZX08007001-002)the National Natural Science Foundation of China(31671286,31672397,31771374)+2 种基金Shandong Provincial Natural Science Foundation for Distinguished Young Scholars of China(JQ201709)the Program of National Cow Industrial Technology System of China(CARS-37)the Shandong Provincial Key Research and Development Program of China(2017GNC10120).
文摘F-box and WD-40 domain protein 11(FBXW11)is an important component of the E3 ubiquitin-ligase enzyme that plays a key role in the ubiquitin-dependent regulation of spermatogenesis.In our previous research,the mRNA expression of FBXW11 in bull sperm with high motility is significantly higher than that with low motility.In the present study,the protein expression levels of FBXW11 in bull testicular tissues with low-performance sperm quality groups were significantly higher than those in normal performance groups.The immunohistochemistry result demonstrated that FBXW11 protein was located in the periphery of Leydig cells and seminiferous tubules.Three splice variants of the FBXW11 gene,namely,FBXW11-tv1,FBXW11-tv2,and FBXW11-tv3,were identified in testicular tissues.The splicing patterns of the three variants are exon skipping.The transcript FBXW11-tv2 expressions were the highest in each sample.The low-performance groups displayed higher FBXW11-tv1 and FBXW11-tv2 transcript expressions than the normal performance groups.Two CpG islands were located within the 5’UTR and exon 1-2 region of the FBXW11 gene.Bisulfite sequencing PCR results demonstrated that the methylation levels of 11 methylation sites in the CpG island 2 from−99 to−43 in the normal performance groups were significantly lower than those in the low-performance groups.Pearson correlation analysis suggested that the CpG island 2 methylation level was negatively correlated with sperm motility and the transcript FBXW11-tv2 expression level.Our data revealed that alternative splicing and DNA methylation jointly regulated FBXW11 gene expression and were correlated with sperm quality traits during spermatogenesis in Holsteins.
